Physiologists have long recognized that the hypothalamus controls all the secretory functions of the adenohypophysis with the hypothalamus producing special polypeptides which trigger the secretion of each pituitary hormone. A hypothalamic releasing factor has been characterized for the pituitary hormones luteinizing hormone, follicular stimulating hormone, thyrotropin and adrenocorticotropin.
Several important hormones are produced in the mammalian hypothalamus and in the anterior lobe of the pituitary gland. One such important hormone is growth hormone which promotes mammalian growth. It has been established that release of growth hormone by the pituitary is subject to regulation by hypothalamic peptides. The concept has been well established that a substance produced in the hypothalamus, referred to as growth hormone releasing factor (GRF) or somatocrinin, promotes the release of growth hormone (GH). Somatostatin, another hypothalamic peptide, is the antagonist of somatocrinin, inhibiting the release of GH from the pituitary.
Although GRF is generally associated with the hypothalamus, it may be produced ectopically by other cells such as pancreatic tumor cells. The sequence of GRF for human pancreatic tumors has been determined (Guillemin, et al., Science, 218, 585-587 (1982)). It is believed that human pancreatic GRF is identical to human hypothalamic GRF [Bohlen, et al., Biochem. and Biophys. Res. Commun., 144, 3, 930-936 (1983)]. Bovine, rat and porcine GRF peptides have also been isolated and sequenced, [Esch, et al., Biochem. Biophys. Res. Commun., 117, 772 (1983) and references therein].
It is the purpose of this invention to provide novel GRF-analog peptides having either increased GRF activity or competitive inhibiting activity. This is accomplished by substituting for the position 1 or 2 amino acyl residue in a GRF-analog peptide or GRF-analog peptide fragment a N,N'-dialkyl substituted argininyl or homoarginyl residue or an analog thereof or .omega.-nitrogen alkyl substituted lysyl analogs.